Nanomicellar Formulation for Synergistic Targeting of Prostate Cancer

用于协同靶向前列腺癌的纳米胶束制剂

• 批准号: 8530621
• 负责人: Song Li
• 金额: $ 19.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8530621
• 关键词: Address; American; Animal Model; Anti-Inflammatory Agents; Antidiabetic Drugs; Benzoquinones; Biodistribution; Camptothecin; Cancer Etiology; Castration; Chemicals; Data; Development; Diagnosis; Drug Formulations; Drug Kinetics; Drug resistance; Embelia; High Pressure Liquid Chromatography; Hormones; Human; Hydroxyl Radical; Lead; Ligands; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Methods; Micelles; Modeling; Mus; PC3 cell line; Paclitaxel; Patients; Pharmaceutical Preparations; Preparation; Refractory; Regimen; Resistance; Ribes; Second Primary Neoplasms; Solubility; Spectrometry, Mass, Electrospray Ionization; System; Therapeutic; Therapeutic Effect; Toxic effect; Treatment outcome; Water; base; cancer cell; cancer type; effective therapy; embelin; hormone refractory prostate cancer; human BIRC4 protein; improved; in vitro activity; in vivo; inhibitor-of-apoptosis protein; male; mortality; neoplastic cell; novel; overexpression; public health relevance; sigma-2 receptor; small molecule; targeted delivery

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the most commonly diagnosed malignancy, and the second leading cause of cancer mortality among American males. Although majority of patients with metastatic PCa initially respond to chemical or surgical castration, a significant number will eventually advance to hormone-refractory PCa (HRPC), for which effective treatment is very limited. Paclitaxel (PTX) is a key component of many therapeutic regimens for HRPC. However, the therapeutic potential of PTX is limited by the associated toxicity. In addition, drug resistance may eventually occur in most of the treated patients. Development of a strategy that can simultaneously improve selective delivery of PTX to tumor cells and sensitize the cancer cells to PTX is likely to significantly improve the outcome of the treatment. We have recently developed a novel delivery system that is based on PEG-derivatized embelin. Embelin is a naturally occurring alkyl substituted hydroxyl benzoquinone and a major constituent of Embelia ribes BURM. It shows antitumor activity by itself and sensitizes resistant cancer cells to other chemodrugs largely thorough blocking the activity of X-linked inhibitor of apoptosis protein (XIAP). Like many other chemodrugs, embelin is poorly water soluble. We found that PEG-derivatized embelin, which is developed in our group by total synthesis, forms small-sized micelles (20-30 nm) and shows significantly increased solubility (>200 mg/mL). More importantly, PEG-embelin becomes a highly efficient solubilizing agent for other compounds including PTX and camptothecin. We hypothesize that PEG-embelin conjugates can serve as a safe and dual functional carrier system to achieve additive or synergistic antitumor effect with co-delivered drugs such as PTX. Indeed, our preliminary data showed that delivery of PTX via PEG-embelin micelles led to significant improvement in antitumor activity in vitro and in vivo. This application is focused on examining if the delivery system can be further improved via conjugation with a small molecule ligand for sigma 2 receptor that is overexpressed in various types of cancers including PCa. Two specific aims will be pursued in this proposal: Aim 1: To determine the targeting efficiency and in vivo biodistribution of PTX formulated in PCa-specific nanomicelles; Aim 2: To investigate the therapeutic effect of PTX formulated in PCa-specific nanomicelles in an animal model of human PCa. Successful completion of this study may lead to the development of a novel therapy to advance the treatment of prostate cancer.

描述（由申请人提供）：前列腺癌（PCa）是最常见的恶性肿瘤，也是美国男性癌症死亡的第二大原因。虽然大多数转移性PCa患者最初对化学或手术去势有反应，但大量患者最终将进展为难治性PCa（HRPC），对此有效治疗非常有限。紫杉醇（PTX）是许多HRPC治疗方案的关键组成部分。然而，PTX的治疗潜力受到相关毒性的限制。此外，大多数接受治疗的患者最终可能会出现耐药性。开发一种策略，可以同时提高PTX向肿瘤细胞的选择性递送和癌细胞对PTX的敏感性，可能会显著改善结果 的治疗。我们最近开发了一种基于PEG衍生的恩贝林的新型递送系统。Embelin是一种天然存在的烷基取代的羟基苯醌，是Embelia ribes BURM的主要成分。它本身显示出抗肿瘤活性，并在很大程度上通过阻断X连锁凋亡抑制蛋白（XIAP）的活性使耐药癌细胞对其他化疗药物敏感。与许多其他化学药物一样，恩贝林水溶性差。我们发现，PEG衍生的恩贝林，这是在我们的小组开发的全合成，形成小尺寸的胶束（20-30 nm），并显示出显着增加的溶解度（>200 mg/mL）。更重要的是，PEG-恩贝林成为其他化合物（包括PTX和喜树碱）的高效增溶剂。我们假设PEG-恩贝林偶联物可以作为一种安全的双功能载体系统，与共递送药物如PTX一起实现相加或协同的抗肿瘤作用。事实上，我们的初步数据显示，通过PEG-恩贝林胶束递送PTX导致体外和体内抗肿瘤活性的显著改善。该申请集中于检查是否可以通过与在包括PCa的各种类型的癌症中过表达的σ 2受体的小分子配体缀合来进一步改进递送系统。本提案将追求两个具体目标：目标1：确定配制在PCa特异性纳米胶束中的PTX的靶向效率和体内生物分布;目标2：研究配制在PCa特异性纳米胶束中的PTX在人PCa动物模型中的治疗效果。这项研究的成功完成可能会导致开发一种新的治疗方法，以促进前列腺癌的治疗。